Drug therapy in elderly patients is often inappropriate, resulting in a high incidence of adverse drug responses, because of poorly defined age-related alterations in drug responsiveness. The University of Arizona provides a unique setting for a broadly based research program into the factors responsible for the special pharmacological problems of aging, but requires an initial research stimulus to generate interest in this important aspect of basic research. The research proposal is to investigate systematially age-related changes in gastrointestinal motility, gastrointestinal drug absorption, hepatic metabolism, plasma half-life, penetration into the brain and responsiveness of brain target tissues. At a more sophisticated level, the fundamental causes of age-related changes in hepatic function which may alter drug metabolism and affect drug binding to plasma proteins will be investigated. Specifically, we will examine the diurnal variation of hepatic RNA polymerases with respect to age, relationship of drug metabolism to hepatic content of smooth endoplasmic reticulum, and age-related changes in hepatic nuclear enzyme activities. Thus, we will approach the problem simultaneously from one point of "what are the effects of age?" and from another of "what factors are responsible for age-related changes?"